High-frequency deep brain stimulation of the subthalamic nucleus (HF STN-DBS) is now the most frequently practiced surgical therapy for the treatment of Parkinson's disease (PD) with more than 20,000 patients having received this treatment as of 2006. However, the clinical use of this treatment has proceeded without a complete understanding of the mechanism of action responsible for alleviation of PD symptomology, as well as the impact of HF STN-DBS on the progression of the disease. The efficacy of HF STN-DBS in the relief of the cardinal motor symptoms of PD is well-documented. However, it has recently been proposed that HF STN-DBS may also actually halt or slow the progression of neurodegeneration in PD, providing neuroprotection to the dopamine (DA) neurons in the substantia nigra (SN). This hypothesis has been supported by preclinical studies demonstrating that HF STN-DBS provides significant protection to the SN DA neurons following the administration of DA-depleting neurotoxins. While these findings are significant, these studies failed to examine the effects of HF STN-DBS on DA terminal density and neurochemistry in the striatum and therefore our understanding of the scope of this neuroprotection is incomplete. Additionally, interpretation of the clinical relevancy of these results is confounded by the fact that neuroprotection of a relatively intact nigrostriatal system was demonstrated, as stimulation was initiated either immediately prior to or immediately following toxin administration. Therefore, it is unknown whether HF STN-DBS can provide neuroprotection for a nigrostriatal system in which the magnitude of DA neuron loss is comparable to the degree of cell loss in PD. Furthermore, these studies did not address the mechanism of HF STN-DBS mediated neuroprotection. Our long-term goal is to characterize the magnitude and elucidate the mechanism of HF STN-DBS mediated neuroprotection in order to optimize this treatment for PD. The objective of this proposal is to determine the effects of long-term HF STN-DBS on SN DA neuron number, degree of striatal dopaminergic innervation and levels of striatal DA and DA metabolites. The temporal relationship between the timing of HF STN-DBS and the neuroprotective potential of HF STN-DBS will be investigated. Further, we seek to determine the role of trophic factor upregulation in these neuroprotective effects. The central hypothesis of this proposal is that long-term HF STN-DBS will provide neuroprotection for both the DA neurons and DA terminals via an upregulation of trophic factor expression. The results of these studies have the potential to inform the optimal therapeutic timing for intervention with STN-DBS as well as to identify a neuroprotective mechanism to be harnessed via this therapy.